Our prior research suggests that serotonergic mechanisms are involved in the pathophysiology of seasonal affective disorder (SAD) and the therapeutic action of light therapy. Given abnormal activation-euphoric responses to the serotonin agonist m-chlorophenylpiperazine (m-CPP) in patients with SAD, we tested the hypothesis that SAD patients would also exhibit abnormal cerebral metabolic responses to this drug, as measured by positron emission tomography (PET) scanning. Results confirmed previous findings of activation-euphoria in patients compared to controls following m-CPP administration. We found no global differences in cerebral metabolism in patients as compared to controls either at baseline or following the drug challenge. The possibility of regional cerebral metabolic differences in patients await future data analysis. In a second PET scan study we tested the hypotheses that (1) one hour of light therapy would tend to normalize the level of blood flow in limbic and paralimbic regions of the brain and exert no effect on controls and (2) the antidepressant response to light therapy following one hour of exposure will correlate with the antidepressant response after one and two weeks of light therapy. Results await future data analysis. To investigate whether the antidepressant effects of light therapy might occur through either serotonergic or catecholaminergic mechanisms, patients remitted on light therapy underwent independent depletions of serotonin and catecholamines. Serotonin and catecholamines were depleted with a tryptophan-free amino acid beverage (plus amino acid capsules) and the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine. Both depletion procedures, compared to sham depletion, equally reversed the antidepressant effects of light therapy. In ongoing studies of lymphoblastoid cell lines, we have attempted to find abnormal polymorphisms in genes related to serotonergic functioning in SAD patients. We have found that the short allele of the 5-HT transporter-linked polymorphism (5-HTTLPR) is associated with SAD, as well as with greater levels of seasonality (seasonally-related behavioral changes such as mood, energy, appetite) in patients with SAD.